Re-sensitizing ER-Alpha Mutant Breast Cancer Cells to Hormonal Therapy

摘要 大多数乳腺癌患者雌激素受体(ERα)呈阳性。在激素治疗的同时 改善约一半ERα阳性乳腺癌患者的临床结果，无论是初治还是后天 耐药性是一个重大的临床挑战。在几个潜在的机制中，热点 已知ERα的突变由于其雌激素非依赖性转录而产生治疗耐药 活动。因此，减轻这些ERα突变体的异常转录活性有望克服 ER-α阳性乳腺癌治疗的耐药性。作为急诊室大家庭的第二位成员， 内质网β能够通过异源二聚和/或竞争共同的方式干扰ERα的活性 染色质结合部位。ERα的这种ERβ干扰功能可以被用来克服 治疗耐药的ERα突变体。然而，这种方法的临床可行性还远远没有得到充分的探索，因为 关于ERα干扰ERβ活性是如何被动员的，目前还知之甚少。 我们的初步工作在ERβ中发现了一个重要的磷酸酪氨酸开关。具体来说， 我们发现，未磷酸化的ERβ在异二聚化和功能干扰方面特别有效 和ERα一起。因此，我们假设非磷酸化ERβ在ERα阳性乳腺癌中可能有帮助 克服ERα突变介导的治疗耐药。我们进一步设想，药理制剂 微调ERβ的磷酸化酪氨酸状态可能有助于临床刺激其ERα干扰 活动。我们将通过两个具体的目标来检验这一新的假设。首先，我们将使用体外和患者- 确定ERβ磷酸化状态对ERα介导的治疗的影响的衍生异种移植模型 抵抗。第二，我们将使用分子和药理学工具来阐明 ERβ的磷酸化状态调节ERα/β的串扰。 通过聚集特定形式的ERβ来克服治疗耐药性的概念代表了一种 新奇的概念。此外，由于磷酸酪氨酸开关上游激酶的抑制剂是 临床上可用的ERβ特异性激动剂在人类中耐受性良好，我们的工作提供了 微调ERβ活性的可用药靶点和治疗ERα阳性乳腺的迫在眉睫的可译性 癌症。我们提出的研究承诺在理解如何 克服激素治疗的治疗阻力，这是乳腺癌治疗中的一个紧迫的临床挑战。

ABSTRACT The majority of breast cancer cases are estrogen receptor (ERα)-positive. While hormonal therapy improves clinical outcomes for about half of patients with ERα-positive breast cancer, de novo or acquired resistance represents a significant clinical challenge. Among several underlying mechanisms, hot-spot point mutants of ERα are known to confer therapeutic resistance due to their estrogen-independent transcriptional activity. Thus, mitigating aberrant transcription activity of these ERα mutants holds promise for overcoming therapeutic resistance in treatment of ERα-positive breast cancer. As the second member of the ER family, ERβ is capable of interfering with ERα activity through heterodimerization and/or competing for common chromatin binding sites. This ERα-interfering function of ERβ could be utilized to overcome the activity of therapeutically resistant ERα mutants. However, clinical feasibility of this approach is vastly under-explored, as little is known about how ERα-interfering activity of ERβ is mobilized. Our preliminary work discovered a functionally important phosphotyrosine switch in ERβ. Specifically, we found that unphosphorylated ERβ is particularly potent in heterodimerization and functional interference with ERα. We therefore hypothesize that unphosphorylated ERβ in ERα-positive breast cancer can help overcome ERα mutant-mediated therapeutic resistance. We further envision that pharmacological agents that fine-tune the phosphotyrosine status of ERβ could be clinically useful in stimulating its ERα-interfering activity. We will test this novel hypothesis through two Specific Aims. First, we will use in vitro and patient- derived xenograft models to determine the impact of ERβ phosphorylation status on ERα-mediated therapeutic resistance. Second, we will use molecular and pharmacological tools to elucidate the mechanism by which ERβ phosphorylation status regulates the ERα/β crosstalk. The concept of overcoming therapeutic resistance by rallying a particular form of ERβ represents a novel concept. Furthermore, because the inhibitor of the upstream kinase for the phosphotyrosine switch is clinically available and ERβ-specific agonists are well tolerated in humans, our work provides multiple druggable targets for fine-tuning ERβ activities and imminent translatability for treating ERα-positive breast cancer. Our proposed study promises both conceptual and translational advances in understanding of how to overcome therapeutic resistance to hormonal therapy, a pressing clinical challenge in breast cancer treatment.